New hope for cataract patients: scientists disrupt fibrosis pathway

Cataracts are a leading cause of vision loss worldwide, and fibrosis-related complications after surgery often limit full recovery. In a new study, researchers have identified NR2F1, a nuclear receptor protein, as a key driver of lens epithelial cell death and fibrotic plaque formation. The team found that impaired autophagy causes abnormal accumulation of NR2F1, which in turn activates the STAT3 signaling pathway—triggering fibrosis, apoptosis, and the progression of cataracts. Remarkably, silencing NR2F1 in cells and mouse models not only suppressed these pathological features but also significantly reduced lens opacity. These findings position NR2F1 as a compelling target for next-generation cataract therapies.

Cataracts remain one of the most prevalent and debilitating eye conditions, often requiring surgical intervention to restore sight. Yet even after surgery, many patients develop anterior subcapsular cataracts (ASC), characterized by fibrotic tissue growth beneath the lens capsule. This complication arises from epithelial-mesenchymal transition (EMT), a process where lens epithelial cells acquire migratory, fibrotic traits. While transforming growth factor-beta (TGF-β) is known to drive this transition, the downstream molecular mechanisms remain elusive. Emerging evidence suggests that transcription factors like NR2F1 may play a role in fibrosis across tissues. Due to these challenges, there is a pressing need to investigate molecular regulators that drive EMT and fibrotic cataracts.

In a recent study (DOI: 10.1016/j.gendis.2025.101549) led by scientists at Chongqing Medical University and Chongqing General Hospital, researchers uncovered a novel regulatory axis driving cataract-associated fibrosis. The findings, published on January 28, 2025, in Genes & Diseases, reveal that NR2F1 promotes fibrosis by directly activating the STAT3 signaling pathway. Using both TGF-β1-treated human lens epithelial cells and a mouse model of ASC, the team discovered that defective autophagy boosts NR2F1 protein accumulation, fueling cell death and fibrotic plaque formation. The research not only identifies a new molecular mechanism behind cataract progression but also highlights potential therapeutic targets for intervention.

The researchers began by confirming elevated NR2F1 protein levels in cataract-affected lens tissues and TGF-β1-stimulated human lens epithelial cells. While mRNA levels of NR2F1 dropped, its protein levels rose—suggesting post-transcriptional dysregulation. Further investigation revealed that impaired autophagy, a cellular cleanup process, was responsible for NR2F1 protein buildup. Blocking autophagy in cells mimicked the TGF-β1 effect, reinforcing this link.

Functionally, silencing NR2F1 dramatically suppressed the EMT process, reduced expression of fibrotic markers (FN1, VIM, α-SMA), and curbed cell migration and apoptosis. In ASC mouse models, injection of an NR2F1-silencing AAV led to visibly clearer lenses and fewer fibrotic plaques. Mechanistic experiments revealed that NR2F1 directly binds to the promoter of STAT3, triggering its phosphorylation and downstream activation.

The team validated the significance of this interaction by using a p-STAT3 inhibitor, which successfully reduced fibrotic and apoptotic markers. These findings suggest that the NR2F1–STAT3 axis is a central driver of fibrosis in cataract formation, operating through autophagy disruption and transcriptional reprogramming. This dual insight—both mechanistic and therapeutic—provides a promising direction for combating fibrotic cataracts beyond current surgical solutions.

“Our study uncovers a critical link between autophagy dysfunction and fibrotic cataract formation,” said Prof. Wenjuan Wan, senior author of the study. “By identifying NR2F1 as a direct activator of the STAT3 pathway, we've revealed a powerful mechanism that fuels lens fibrosis and cell death. What's most exciting is the translational potential—by blocking this pathway, we were able to significantly reverse cataract symptoms in animal models. This opens up new possibilities for non-surgical therapies targeting the root molecular causes of lens opacification.”

The identification of the NR2F1–STAT3 signaling pathway as a driver of cataract-associated fibrosis holds significant clinical potential. Current treatments rely heavily on surgery, yet fibrotic complications frequently recur and impair long-term outcomes. By targeting NR2F1, it may be possible to develop pharmaceutical agents that prevent fibrosis at the molecular level—either as stand-alone therapies or as adjuncts to surgery. Beyond cataracts, the NR2F1–STAT3 axis may also be relevant to other fibrotic diseases, offering broad implications across fields like oncology and tissue regeneration. Continued research is essential to validate these findings in clinical settings and to translate them into patient-centered solutions.

###

References

DOI

10.1016/j.gendis.2025.101549

Original Source URL

https://doi.org/10.1016/j.gendis.2025.101549

Funding information

This work was supported in part by grants from the National Natural Science Foundation of China (No. 81870650, 82371098, 81970832, 81900885), the Natural Science Foundation Project of Chongqing, China (No. cstc2021jcyj-msxm3178), the Project Foundation of Chongqing Science and Technology Commission of China (No. cstc2021jscx-gksb-N0017, cstc2020jcyj-msxmX0829, cstc2021jcyj-msxmX0967, CSTB2022NSCQ-MSX1561) and the National Key Research and Development Program of China (No. 2020YFC2008200, 2020YFC2008204).

About Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Emphasis will be placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases.